Integrated in silico and in vivo approaches to investigate effects of BDE‐99 mediated by the nuclear receptors on developing zebrafish

• Published in: Environmental toxicology and chemistry 2018-03, Vol.37 (3), p.780-787
• Main Authors: Zhang, Li, Jin, Yaru, Han, Zhihua, Liu, Hongling, Shi, Laihao, Hua, Xiaoxue, Doering, Jon A., Tang, Song, Giesy, John P., Yu, Hongxia
• Format: Article
• Language: English
• Subjects: Animals; Aromatic compounds; Aryl hydrocarbon receptor; Binding Sites; Bioaccumulation; Computer Simulation; Cross‐talk; Danio rerio; Docking; Ecological risk assessment; Environmental assessment; Environmental risk; Ethers; Fish; Gene Expression Profiling; Gene Expression Regulation, Developmental - drug effects; Gene Regulatory Networks - drug effects; Genes; Glucocorticoids; Halogenated Diphenyl Ethers - toxicity; In vivo methods and tests; Molecular Docking Simulation; Molecular dynamic simulation; Molecular Dynamics Simulation; Nuclear receptors; Polybrominated diphenyl ethers; Pregnane X receptor; Receptors; Receptors, Cytoplasmic and Nuclear - metabolism; Risk assessment; Signaling; Studies; Thyroid; Transcription; Transcription, Genetic - drug effects; Vertebrates; Wildlife; Zebrafish; Zebrafish - embryology; Zebrafish - genetics; Zebrafish - metabolism; Zebrafish Proteins - chemistry; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0730-7268; 1552-8618
• DOI: 10.1002/etc.4000

One of the most abundant polybrominated diphenyl ethers (PBDEs) is 2,2′,4,4′,5‐pentabromodiphenyl ether (BDE‐99), which persists and potentially bioaccumulates in aquatic wildlife. Previous studies in mammals have shown that BDE‐99 affects development and disrupts certain endocrine functions through signaling pathways mediated by nuclear receptors. However, fewer studies have investigated the potential of BDE‐99 to interact with nuclear receptors in aquatic vertebrates such as fish. In the present study, interactions between BDE‐99 and nuclear receptors were investigated by in silico and in vivo approaches. This PBDE was able to dock into the ligand‐binding domain of zebrafish aryl hydrocarbon receptor 2 (AhR2) and pregnane X receptor (PXR). It had a significant effect on the transcriptional profiles of genes associated with AhR or PXR. Based on the developed cytoscape of all zebrafish genes, it was also inferred that AhR and PXR could interact via cross‐talk. In addition, both the in silico and in vivo approaches found that BDE‐99 affected peroxisome proliferator–activated receptor alpha (PPARα), glucocorticoid receptor, and thyroid receptor. Collectively, our results demonstrate for the first time detailed in silico evidence that BDE‐99 can bind to and interact with zebrafish AhR and PXR. These findings can be used to elaborate the molecular mechanism of BDE‐99 and guide more objective environmental risk assessments. Environ Toxicol Chem 2018;37:780–787. © 2017 SETAC BDE‐99 was drawn by ChemBioDraw (ChemBioOffice 2008, CambridgeSoft, Corp., USA). In the part of “in silico investigations”, the picture of NRs and the interaction between BDE‐99 and z‐AhR2, z‐PXR were generated and captured in PyMol (Version 0.99, open source), and the plot of RMSDs was generated by Origin 8 (OriginLab Corp, Northampton, MA, USA). The pictures of “in vivo investigations” were taken in the State Key Laboratory of Pollution Control and Resource Reuse at School of the Environment of Nanjing University. The panoramic map of signaling pathways was integrated within Cytoscape software v3.1.1 (Cytoscape consortium, San Diego, CA, USA). Morphology effects on embryos/larvae were taken by an inverted stereomicroscope in the State Key Laboratory of Pollution Control and Resource Reuse at School of the Environment of Nanjing University. All pictures were either drawn or taken by the authors of this study.